Tocilizumab for Chronic Graft-versus-Host Disease Treatment

PRIMARY OBJECTIVES:

I. Efficacy will be determined by the proportion of patients with failure free survival
(FFS) at 6 months.

SECONDARY OBJECTIVES:

I. Patients achieving a complete response (CR) or partial response (PR) at 6 months based on
clinician judged response.

II. Patients achieving a CR or PR by objective response measures at 6 months.

III. Failure-free survival (FFS) at 1 year.

IV. Change in steroid dose from enrollment to 6 months (mo).

TERTIARY OBJECTIVES:

I. Biologic studies will be done to determine possible mechanisms of response.

OUTLINE:

Patients receive tocilizumab intravenously (IV) over 1 hour every 2 weeks for 12 weeks
(weeks 1, 3, 5, 7, 9, and 11) and then every 4 weeks for 12 weeks (weeks 13, 17, and 21).

After completion of study treatment, patients are followed up at 3 and 6 months.

Inclusion Criteria:

- Subject has moderate or severe overlap chronic (c)GVHD according to National
Institutes of Health (NIH) criteria

- Active cGVHD despite treatment with at least two immunosuppressive treatments (not
including GVHD prophylaxis) in the past year

- Subject underwent allogeneic stem cell transplantation at least 6 months prior to
enrollment

- Subject has not started any new systemic immunosuppressive therapies within 2 weeks
prior to enrollment

- Female subjects of child bearing potential must have a negative pregnancy test prior
to first dose of tocilizumab and must agree to practice effective contraception
during the study

- Subject meets the following medication restriction requirements and agrees to follow
medication restrictions during the study; the following concomitant medications are
not allowed: cyclophosphamide, abatacept, etanercept, adalimumab infliximab,
golimumab, tofacitinib, and alemtuzumab; these medications also cannot have been used
for 5 half-lives prior to enrollment

- Subject agrees to comply with the study requirements and agrees to come to the clinic
for required study visits

Exclusion Criteria:

- Donor lymphocyte infusion in the preceding 100 days

- Subject has bronchiolitis obliterans, bronchiolitis obliterans with organizing
pneumonia or cryptogenic organizing pneumonia as the sole manifestation of cGVHD

- Uncontrolled bacterial, viral infection or invasive fungal infection

- Evidence of malignancy within 6 months of study enrollment; this is defined as clear
morphologic, radiologic or molecular evidence of disease; mixed chimerism is allowed
at the discretion of the clinician

- Treatment with any non-Food and Drug Administration (FDA) approved agent within 4
weeks (or 5 half-lives of the investigational drug, whichever is longer) of study
enrollment

- Immunization with a live, attenuated vaccine within 4 weeks prior to study enrollment

- History of severe allergic or anaphylactic reactions to human, humanized or murine
monoclonal antibodies

- Tuberculosis requiring treatment within the past 3 years; all patients must have a
negative quantiferon test within 4 weeks prior to starting study drug

- Pregnant or breast-feeding women

- Patients (both men and women) with reproductive potential not willing to use an
effective method of contraception

- Serum creatinine > 1.6 mg/dL (141 umol/L) in females and > 1.9 mg/dL (168 umol/L) in
males; patients with serum creatinine values exceeding these limits are eligible for
the study if their estimated glomerular filtration rates (GFR) are > 30 ml/min/1.73
m^2

- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 times upper
limit of normal (ULN)

- Total bilirubin > upper limit of normal (ULN)

- Absolute neutrophil count < 1.5 x 10^9/L (1500/mm^3)

- Known active hepatitis B or C; patients must have a negative test for hepatitis B
surface antigen, hepatitis B core antibody and hepatitis C antibody within 4 weeks
prior to starting study drug

- Known uncontrolled cytomegalovirus (CMV) polymerase chain reaction (PCR) reactivation
per institutional standards; once CMV has been treated and stable per institutional
standards, patient may be enrolled; CMV PCR will be tested within two weeks prior to
starting study drug

- History of diverticulitis, Crohn's disease or ulcerative colitis

- History of demyelinating disorder